Discovery of a redox-thiol switch regulating cellular energy metabolism

Gao, Xin; L, Li; Parisien, Marc; McLeod, Matthew; Wu, Jianrong; Bederman, Ilya; Krokowski, Dawid; Sm, Chirieleison; Diatchenko, Luda; Abbott, Derek W.; Yee,; Cl, Hoppel; Rg, Kibbey; Holyoak, Todd; Willard, Belinda; Arvan, Peter; Hatzoglou, Maria

doi:10.1101/520411

Cited by 3 publications

(3 citation statements)

References 47 publications

(87 reference statements)

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“…Cys55 could form a disulfide bond with Cys151, which would be ≈3Å apart. The enzyme is inactivated by glutathionylation of Cys306, which is close to the active site, in a way reversed by SH2 [54]. We have detected this cysteine in all the samples in a highly reduced state (red/ox > 20) insensitive to Prdx6 silencing, allowing for full activity (Supplementary File S2).…”

Section: Resultsmentioning

confidence: 93%

Peroxiredoxin 6 Down-Regulation Induces Metabolic Remodeling and Cell Cycle Arrest in HepG2 Cells

et al. 2019

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Peroxiredoxin 6 (Prdx6) is the only member of 1-Cys subfamily of peroxiredoxins in human cells. It is the only Prdx acting on phospholipid hydroperoxides possessing two additional sites with phospholipase A2 (PLA2) and lysophosphatidylcholine-acyl transferase (LPCAT) activities. There are contrasting reports on the roles and mechanisms of multifunctional Prdx6 in several pathologies and on its sensitivity to, and influence on, the redox environment. We have down-regulated Prdx6 with specific siRNA in hepatoblastoma HepG2 cells to study its role in cell proliferation, redox homeostasis, and metabolic programming. Cell proliferation and cell number decreased while cell volume increased; import of glucose and nucleotide biosynthesis also diminished while polyamines, phospholipids, and most glycolipids increased. A proteomic quantitative analysis suggested changes in membrane arrangement and vesicle trafficking as well as redox changes in enzymes of carbon and glutathione metabolism, pentose-phosphate pathway, citrate cycle, fatty acid metabolism, biosynthesis of aminoacids, and Glycolysis/Gluconeogenesis. Specific redox changes in Hexokinase-2 (HK2), Prdx6, intracellular chloride ion channel-1 (CLIC1), PEP-carboxykinase-2 (PCK2), and 3-phosphoglycerate dehydrogenase (PHGDH) are compatible with the metabolic remodeling toward a predominant gluconeogenic flow from aminoacids with diversion at 3-phospohglycerate toward serine and other biosynthetic pathways thereon and with cell cycle arrest at G1/S transition.

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Section: Resultsmentioning

confidence: 93%

Peroxiredoxin 6 Down-Regulation Induces Metabolic Remodeling and Cell Cycle Arrest in HepG2 Cells

et al. 2019

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“…A protein that is subject to multiple cysteine modifications (and additionally lysine acetylation and others) will then function as a built-in sensor and mediator to control energy metabolism and to maintain redox-homeostasis under a broad range of challenging situations. Redox-thiol switches were suggested to fine-tune the central pathways of energy metabolism [62], with S-sulfhydration as another intermediate step during metabolic reprogramming when multiple stress factors need to be integrated [63].…”

Section: Discussionmentioning

confidence: 99%

Three cytosolic NAD-malate dehydrogenase isoforms of Arabidopsis thaliana: on the crossroad between energy fluxes and redox signaling

Liszka

Schimpf

Zaruma

et al. 2020

Biochemical Journal

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In yeast and animal cells, mitochondrial disturbances resulting from imbalances in the respiratory chain require malate dehydrogenase (MDH) activities for re-directing fluxes of reducing equivalents. In plants, in addition to mitochondria, plastids use malate valves to counterbalance and maintain redox-homeostasis. Arabidopsis expresses three cytosolic MDH isoforms, namely cyMDH1, cyMDH2, and cyMDH3, the latter possessing an N-terminal extension carrying a unique cysteine residue C2. In this study, redox-effects on activity and structure of all three cyMDH isoforms were analyzed in vitro. cyMDH1 and cyMDH2 were reversibly inactivated by diamide treatment, accompanied by dimerization via disulfide-bridge formation. In contrast, cyMDH3 forms dimers and higher oligomers upon oxidation, but its low specific activity is redox-independent. In the presence of glutathione, cyMDH1 and cyMDH2 are protected from dimerization and inactivation. In contrast, cyMDH3 still dimerizes but does not form oligomers any longer. From analyses of single and double cysteine mutants and structural modeling of cyMDH3, we conclude that the presence of C2 and C336 allows for multiple cross-links in the higher molecular weight complexes comprising disulfides within the dimer as well as between monomers of two different dimers. Furthermore, nuclear localization of cyMDH isoforms was significantly increased under oxidizing conditions in isolated Arabidopsis protoplasts, in particular of isoform cyMDH3. The unique cyMDH3 C2-C2-linked dimer is, therefore, a good candidate as a redox-sensor taking over moonlighting functions upon disturbances of energy metabolism, as shown previously for the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) where oxidative modification of the sensitive catalytic cysteine residues induces nuclear translocation.

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“…In fact, a substrate or protein is transported in a specific redox state to another compartment, where it undergoes oxidative modification (Hosios and Vander Heiden, 2018). Many key enzymes of metabolic pathways can be regulated via specific and reversible oxidative modifications that act as thiol switches (Brandes et al, 2009;López-Grueso et al, 2019;Gao et al, 2020). They are part of redox signaling circuits and depend on i) second messengers like H 2 O 2 , hydrogen sulfide (H 2 S), and NO, and ii) the catalysis by enzymes of the Trx family (including thioredoxins, glutaredoxins, and peroxiredoxins) (Hanschmann, 2013).…”

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confidence: 99%

Redox signaling and metabolism in Alzheimer's disease

Holubiec

Gellert

Hanschmann³

2022

Front. Aging Neurosci.

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Reduction and oxidation reactions are essential for biochemical processes. They are part of metabolic pathways and signal transduction. Reactive oxygen species (ROS) as second messengers and oxidative modifications of cysteinyl (Cys) residues are key to transduce and translate intracellular and intercellular signals. Dysregulation of cellular redox signaling is known as oxidative distress, which has been linked to various pathologies, including neurodegeneration. Alzheimer's disease (AD) is a neurodegenerative pathology linked to both, abnormal amyloid precursor protein (APP) processing, generating Aβ peptide, and Tau hyperphosphorylation and aggregation. Signs of oxidative distress in AD include: increase of ROS (H2O2, O2•−), decrease of the levels or activities of antioxidant enzymes, abnormal oxidation of macromolecules related to elevated Aβ production, and changes in mitochondrial homeostasis linked to Tau phosphorylation. Interestingly, Cys residues present in APP form disulfide bonds that are important for intermolecular interactions and might be involved in the aggregation of Aβ. Moreover, two Cys residues in some Tau isoforms have been shown to be essential for Tau stabilization and its interaction with microtubules. Future research will show the complexities of Tau, its interactome, and the role that Cys residues play in the progression of AD. The specific modification of cysteinyl residues in redox signaling is also tightly connected to the regulation of various metabolic pathways. Many of these pathways have been found to be altered in AD, even at very early stages. In order to analyze the complex changes and underlying mechanisms, several AD models have been developed, including animal models, 2D and 3D cell culture, and ex-vivo studies of patient samples. The use of these models along with innovative, new redox analysis techniques are key to further understand the importance of the redox component in Alzheimer's disease and the identification of new therapeutic targets in the future.

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Discovery of a redox-thiol switch regulating cellular energy metabolism

Cited by 3 publications

References 47 publications

Peroxiredoxin 6 Down-Regulation Induces Metabolic Remodeling and Cell Cycle Arrest in HepG2 Cells

Peroxiredoxin 6 Down-Regulation Induces Metabolic Remodeling and Cell Cycle Arrest in HepG2 Cells

Three cytosolic NAD-malate dehydrogenase isoforms of Arabidopsis thaliana: on the crossroad between energy fluxes and redox signaling

Redox signaling and metabolism in Alzheimer's disease

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